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TOXICOLOGY II. Toxic compounds in cases of intoxication at present. M. Balíková. Toxicological cases in laboratory. Clinical – examination from reasons : Diagnostics Therapy controls Prevention b) Clinical – forensic development c) Forensic Autopsies (suicides, homicides…) - PowerPoint PPT Presentation
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TOXICOLOGYTOXICOLOGY
II. Toxic compounds in cases of II. Toxic compounds in cases of
intoxication at presentintoxication at present
M. BalíkováM. Balíková
M. Balíková: Toxic compounds 2
Toxicological cases in Toxicological cases in laboratorylaboratory
a)a) Clinical – examination from reasonsClinical – examination from reasons:: DiagnosticsDiagnostics Therapy controlsTherapy controls PreventionPrevention
b)b) Clinical – forensic developmentClinical – forensic developmentc) Forensicc) Forensic
Autopsies (suicides, homicides…)Autopsies (suicides, homicides…) Traffic accidentsTraffic accidents Occupational injuriesOccupational injuries Violence associated with roberies, rapes, Violence associated with roberies, rapes,
injuries…injuries… OthersOthers
M. Balíková: Toxic compounds 3
CLINICAL TOXICOLOGY - SYMPTOMSCLINICAL TOXICOLOGY - SYMPTOMS
Importance of anamnestic data, Importance of anamnestic data, symptomssymptoms
Differential diagnosis – Differential diagnosis – Is it Is it poisoning?poisoning?
Preliminary results – therapeutic Preliminary results – therapeutic actionaction
BUTBUTnonspecific symptoms of intoxicationnonspecific symptoms of intoxication
Gastrointestinal problemsGastrointestinal problems
Cramps (strychnin, cyanides, antidepressants, Cramps (strychnin, cyanides, antidepressants, cocaine…cocaine…
Hallucinations (LSD, psilocybine, MDMA, Hallucinations (LSD, psilocybine, MDMA, cannabis….)cannabis….)
Mydriasis / MiosisMydriasis / Miosis
M. Balíková: Toxic compounds 4
Acute intoxicationsAcute intoxications
Intentional (suicides, homicides, Intentional (suicides, homicides, associated with violence to associated with violence to others)others)
Drug abuseDrug abuseNonintentional (small children, Nonintentional (small children,
accidental ingestion, expositions)accidental ingestion, expositions)
M. Balíková: Toxic compounds 5
FORENSIC TOXICOLOGYFORENSIC TOXICOLOGY
Careful individual attitude Careful individual attitude
Examination in series not Examination in series not commoncommon
Individual optimalization of Individual optimalization of examinationexamination
Principle in toxicologyPrinciple in toxicology::
results results confirmationconfirmation by another by another independent and specific method independent and specific method – if available– if available
The final toxicological evidence – The final toxicological evidence – defensible scientifically and defensible scientifically and legallylegally
M. Balíková: Toxic compounds 6
Frequent toxic Frequent toxic compoundscompounds
in acute intoxicationsin acute intoxicationsEthanolEthanolPharmaceuticalsPharmaceuticalsDrugs of abuseDrugs of abuseCarbon oxideCarbon oxideVolatiles Volatiles GlycolsGlycolsMushrooms, herbal toxinsMushrooms, herbal toxins
M. Balíková: Toxic compounds 7
EthylalcoholEthylalcohol Hydrophilic compound, rapid resorption, in Hydrophilic compound, rapid resorption, in blood blood distributed in favour of plasmadistributed in favour of plasma Pharmacokinetics:Pharmacokinetics:
rate of resorption rate of resorption > > rate of eliminationrate of elimination
elimination with zero order rate elimination with zero order rate (0.12-0.2 g/kg/h)(0.12-0.2 g/kg/h)
Metabolism: 70% alcoholdehydrogenase, 25% Metabolism: 70% alcoholdehydrogenase, 25% MEOS, 5% excreted in parent formMEOS, 5% excreted in parent form
Effects: Narcotic – fat solubility – CNS Effects: Narcotic – fat solubility – CNS depressantdepressant
Endogenous bacterial production (0,001 –Endogenous bacterial production (0,001 –0,002 g/kg)0,002 g/kg) Postmortem production (ethanol and other Postmortem production (ethanol and other alcohols)alcohols)
M. Balíková: Toxic compounds 8
Ethanol blood level and Ethanol blood level and methodsmethods
Breathanalysers – indirect testBreathanalysers – indirect test Gas chromatography – direct Gas chromatography – direct
alcohol measurement in venous alcohol measurement in venous blood, specific forensic methodblood, specific forensic method
Enzymatic method – clinical cases Enzymatic method – clinical cases O. K., but potentional interferences O. K., but potentional interferences (lactate)(lactate)
Widmark method – nonspecific Widmark method – nonspecific (based on reduction of bichromate)(based on reduction of bichromate)
M. Balíková: Toxic compounds 9
Ethanol and drivingEthanol and driving Two general types of legislation in the Two general types of legislation in the
worldworld: : 1) Impairment1) Impairment2) Per2) Per sese
In Czech RepIn Czech Rep. – Impairment type. – Impairment typeJurisdiction: Jurisdiction: 0.2 g/kg cut off value0.2 g/kg cut off value 0.5 g/kg – impairment very probable, 0.5 g/kg – impairment very probable,
administrative sanctionsadministrative sanctions 1.0 g/kg – unfit for driving, dangerous, 1.0 g/kg – unfit for driving, dangerous,
penal proceedings at courtpenal proceedings at court
M. Balíková: Toxic compounds 10
MethanolMethanol
Lethal doses 5 –100 mlLethal doses 5 –100 mlMetabolites: formaldehyde, formic Metabolites: formaldehyde, formic
acidacidVery slow oxidation, max level of Very slow oxidation, max level of
formic acid – 2 days after ingestionformic acid – 2 days after ingestionDangerous delayed effects:Dangerous delayed effects:
at first – narcoticat first – narcoticlater – metabolic acidosis , later – metabolic acidosis ,
retina damage, blindness, deathretina damage, blindness, death
M. Balíková: Toxic compounds 11
Methanol poisoningMethanol poisoning
Antidotum ethanol Antidotum ethanol Competitive alcohols oxidation Competitive alcohols oxidation
(long term ETOH infusion – blood (long term ETOH infusion – blood level maintenance 1.5 g/kg) level maintenance 1.5 g/kg) protection from methanol protection from methanol oxidationoxidation
HaemodialysisHaemodialysisNaHCO3 infusion – correction of pHNaHCO3 infusion – correction of pH
M. Balíková: Toxic compounds 12
Glycols - DiolsGlycols - Diols Intoxications – intentional ,accidentalIntoxications – intentional ,accidental Antifreezers – FRIDEXAntifreezers – FRIDEX Solvents, also vehiculum in some Solvents, also vehiculum in some
pharmaceutical products (injections)pharmaceutical products (injections)Ethanediol and dimers, trimers, Ethanediol and dimers, trimers,
polymerspolymersPropanediol 1,2 and 1,3 isomersPropanediol 1,2 and 1,3 isomersButanediol- precursor of GHBButanediol- precursor of GHBGlycol monoalkyl ethers – brake liquids Glycol monoalkyl ethers – brake liquids
(celosolve, carbitols)(celosolve, carbitols)
M. Balíková: Toxic compounds 13
Ethylene-glycolEthylene-glycolToxic oxidative metabolitesToxic oxidative metabolites::glycolaldehyde, glycolic acid, glyoxylic glycolaldehyde, glycolic acid, glyoxylic
acid, oxalic acidacid, oxalic acidToxic effectsToxic effects:: narcotic (alcohol)narcotic (alcohol) gradual development of acidosisgradual development of acidosis renal failure, anuriarenal failure, anuriaTherapyTherapy as soon as possible – as in as soon as possible – as in
methanol poisoning- ethanol as methanol poisoning- ethanol as antidotum, haemodialysis, natrium antidotum, haemodialysis, natrium bicarbonatebicarbonate
M. Balíková: Toxic compounds 14
Volatiles – CNS Volatiles – CNS depressantsdepressants
HydrocarbonsHydrocarbonsa) gaseous (propane, butane…)a) gaseous (propane, butane…)b) liquid (toluene, chloroform…)b) liquid (toluene, chloroform…)
FuelsFuelsVarious solventsVarious solventsAenesthetics (ether, halothane…)Aenesthetics (ether, halothane…)Intentional or accidental intoxicationsIntentional or accidental intoxicationsDrug abuse by inhalation, euphoria, Drug abuse by inhalation, euphoria,
hallucinationshallucinationsDangerous overdoses, fatal intoxicationsDangerous overdoses, fatal intoxications
M. Balíková: Toxic compounds 15
Volatiles abuseVolatiles abuseChronic abuseChronic abuse:: psychical addictionpsychical addiction hepatorenal toxicityhepatorenal toxicity neurotoxicityneurotoxicity cardiotoxicitycardiotoxicity
Overdose:Overdose:
agitation, cramps, coma, cardiac agitation, cramps, coma, cardiac failure, deathfailure, death
M. Balíková: Toxic compounds 16
Volatiles metabolismVolatiles metabolism Partly expired in parent formPartly expired in parent form Only some produce known metabolites Only some produce known metabolites
into urine (toluene 80-90% hippuric acid, into urine (toluene 80-90% hippuric acid, butane only 1% as 2-butanol)butane only 1% as 2-butanol)
Only some can appear in urine in parent Only some can appear in urine in parent form (aromates)form (aromates)
Some metabolites expired into air Some metabolites expired into air (dichloromethane – 50% CO metabolite)(dichloromethane – 50% CO metabolite)
Useful sample for toxicology – bloodUseful sample for toxicology – blood Method : gas chromatographyMethod : gas chromatography
M. Balíková: Toxic compounds 17
Carbon oxideCarbon oxideBurning of organic compounds Burning of organic compounds
at insuffient access of airat insuffient access of airStrong affinity to haemoglobin Strong affinity to haemoglobin
- in the same molar ratio as - in the same molar ratio as oxygen but 220 times stronger, oxygen but 220 times stronger, competition for binding – even competition for binding – even low traces in air can be low traces in air can be gradually boundgradually bound
Degree of poisoning correlates Degree of poisoning correlates with time of exposition, with time of exposition, physical activitiesphysical activities
M. Balíková: Toxic compounds 18
Carbon oxide cont.Carbon oxide cont.
Toxic effects:Toxic effects: reduction of oxygen transport in blood, reduction of oxygen transport in blood,
neurotoxicity, potentional neurotoxicity, potentional development of Parkinsonism in development of Parkinsonism in chronic expositionchronic exposition
Endogenous levels COHb Endogenous levels COHb < 0.5 < 0.5 %%Smokers up to 10 %Smokers up to 10 %Light intoxication 10-20 % COHbLight intoxication 10-20 % COHbSevere intoxication – 30-40% COHbSevere intoxication – 30-40% COHbComa, respiratory failure 40 –50% COHbComa, respiratory failure 40 –50% COHbFatal 50 –70% COHbFatal 50 –70% COHb
M. Balíková: Toxic compounds 19
CyanidesCyanidesHydrogen cyanide, HCN, boiling point 26° Hydrogen cyanide, HCN, boiling point 26°
C, bitter almond like odor, colorless, very C, bitter almond like odor, colorless, very toxic gas or liquid (hydrocyanic acid)toxic gas or liquid (hydrocyanic acid)
NaCN, KCN unstable in acidic media, NaCN, KCN unstable in acidic media, hydrolysis to toxic HCN, unstable in air – hydrolysis to toxic HCN, unstable in air – carbonatescarbonates
HCN present in exhaust gases, in tobacco HCN present in exhaust gases, in tobacco and wood smoke, in smoke from burning and wood smoke, in smoke from burning nitrogen containing plasticsnitrogen containing plastics
HCN in air300 p.p.b. will kill a human in a HCN in air300 p.p.b. will kill a human in a few minfew min
LD50 in humans very individual (0.005 – 1 LD50 in humans very individual (0.005 – 1 g)g)
M. Balíková: Toxic compounds 20
Cyanides cont.Cyanides cont.BiotransformationBiotransformation in the liver : thiocyanates in the liver : thiocyanates Toxic mechanismToxic mechanism: Inhibition of : Inhibition of
cytochromoxidase, cells can not accept cytochromoxidase, cells can not accept oxygen, tissues hypoxiaoxygen, tissues hypoxia
Therapy:Therapy: administration of compounds with Co or administration of compounds with Co or
Fe(III)Fe(III) Amylnitrite, natrium nitrite as antidotum –Amylnitrite, natrium nitrite as antidotum –
cyanomethaemoglobine production, enzyme cyanomethaemoglobine production, enzyme block releasingblock releasing
Thiosulphate infusion – metabolites SCNThiosulphate infusion – metabolites SCN Oxygen ventilationOxygen ventilation
M. Balíková: Toxic compounds 21
MercuryMercury Metallic form – water insolubleMetallic form – water insoluble Salts – water soluble, partial resorption p. Salts – water soluble, partial resorption p.
o.o. Fine particles in air – dangerous entrance Fine particles in air – dangerous entrance
via lungs into blood, subsequent via lungs into blood, subsequent oxidation, cumulation in the brain, kidney oxidation, cumulation in the brain, kidney – potentional neurotoxicity, nefrotoxicity– potentional neurotoxicity, nefrotoxicity
Elimination into urine – very slowElimination into urine – very slow Organic mercury –lipophilic, molecular Organic mercury –lipophilic, molecular
effects, accumulation in CNS, embryotoxiceffects, accumulation in CNS, embryotoxic Mercury in water sediments – bacteria Mercury in water sediments – bacteria
transformation into organic mercury- transformation into organic mercury- contamination of fish meat - dangerouscontamination of fish meat - dangerous
M. Balíková: Toxic compounds 22
Pesticides-1Pesticides-1
InsecticidesInsecticides HerbicidesHerbicides FungicidesFungicides RhodenticidesRhodenticides
Organic compounds of Organic compounds of various structures, various various structures, various toxic mechanisms, various toxic mechanisms, various symptoms of intoxication, symptoms of intoxication, various effectsvarious effects
Human acute intoxications in EUROPE at present not Human acute intoxications in EUROPE at present not frequentfrequent ORGANOPHOSPHATES (sarin, parathion, ORGANOPHOSPHATES (sarin, parathion, malathion...)malathion...)
CARBAMATES (aldicarb, carbofuran...)CARBAMATES (aldicarb, carbofuran...)
CHLORINATED HYDROCARBONS CHLORINATED HYDROCARBONS (chlophenothane=DDT, (chlophenothane=DDT, lindan, aldrin...)lindan, aldrin...)
BIPYRIDINE DERIVATIVES (paraquat, diquat...)BIPYRIDINE DERIVATIVES (paraquat, diquat...)
ANTICOAGULANS (warfarin, diolan...)ANTICOAGULANS (warfarin, diolan...)
M. Balíková: Toxic compounds 23
Pesticides - 2Pesticides - 2Organophosphates:Organophosphates:
irreversible potent acetylcholinesterase inhibition, irreversible potent acetylcholinesterase inhibition, respiratory difficulties, salivation, miosis, nausea, respiratory difficulties, salivation, miosis, nausea, paralysis...paralysis...antidotum atropineantidotum atropinep-nitrophenol in urine – marker of exposure to parathionp-nitrophenol in urine – marker of exposure to parathion
Carbamates:Carbamates:derivatives of methylcarbamic acidderivatives of methylcarbamic acidreversible inhibition of acetylcholinesterasereversible inhibition of acetylcholinesteraseantidotum atropineantidotum atropine
Polychlorinated hydrocarbons:Polychlorinated hydrocarbons: free radicals by biotransformationfree radicals by biotransformation
convulsions, nausea; chronic neurotoxicity, hepato and convulsions, nausea; chronic neurotoxicity, hepato and nefrotoxicitynefrotoxicity
Bipyridine derivatives: Bipyridine derivatives: paraquat, diquat (GRAMOXONE, ATRAZINE)paraquat, diquat (GRAMOXONE, ATRAZINE)
contact toxicity, inflamation, bleeding, local necrosis, contact toxicity, inflamation, bleeding, local necrosis, muscle stiffness, blurred vision, pulmonary fibrosismuscle stiffness, blurred vision, pulmonary fibrosis
Anticoagulants:Anticoagulants:warfarin, diolan (KUMATOX, TALON-G)warfarin, diolan (KUMATOX, TALON-G)
M. Balíková: Toxic compounds 24
PharmaceuticalsPharmaceuticalsAccidental and intentional overdoses, suicides Accidental and intentional overdoses, suicides Combination with alcohol, mixtures of drugsCombination with alcohol, mixtures of drugsDrug abuse – narcotic and psychotropic substancesDrug abuse – narcotic and psychotropic substances
Mostly organic substances with low molecular mass up to 400 Mostly organic substances with low molecular mass up to 400 DaltonsDaltons
ClassificationClassification::1) 1) StructureStructure – important for analytical toxicology, laboratory – important for analytical toxicology, laboratory attitudeattitude2) 2) ATC system (WHO) – Anatomical-Therapeutical-Chemical ATC system (WHO) – Anatomical-Therapeutical-Chemical ::
A – Gastrointestinal tract (spasmolytics, anticholinergics….)B – Blood systemC – Cardiovascular system (cardiotonica, , antihypertensiva……)D, G, H – Dermatologica, urologica, gynekologica, hormonesJ, L – Antibacterials, antivirotics, antimycotica, cytostaticaM – Muscle-sceletal system (antirevmatica, antiphlogistica,
myorelaxancia)N – Neurological system
(anestetica,analgesica,antiepileptica,psycholeptica)P – AntiparasiticaR – Respiratory system (antiasthmatica, antitusica,
antihistaminica…..)S, V – Varia
A C M N R – significant participation in drug overdose cases
M. Balíková: Toxic compounds 25
BarbituratesBarbiturates
BarbiturátyBarbiturátyPsychotropic substances – CNS suppressionThe first derivative at the market – barbitalCommon structure of various derivatives - barbiruric acidAcidic character – after p. o. resorption mainly in small intestine
Variable effect duration, therapeutic indicationVariable effect duration, therapeutic indication:
Short time effect – pentobarbital halflife 20-30 h)Long time effect – phenobarbital halflife 2-6 days)
Thiobarbital (thiopental) – i. v. anestheticumThiobarbital, pentobarbital – intracranial pressure reduction Phenobarbital – sedative, antiepilepticsVarious barbiturates in pharmaceutical composites, analgesics, antiphlogistics (Spasmoveralgin, Alnagon,Bellaspon, Dinyl, Eunalgit……)
At present – less prescription due to significant mortality at overdose, replacement by more safe substances
M. Balíková: Toxic compounds 26
BenzodiazepinesBenzodiazepinesPsychotropic substances with CNS sedationPsychotropic substances with CNS sedation
Frequent therapeutical indication Frequent abuse (sometimes with alcohol or illegal drugs) Potential criminal misuse
More than 30 various structures with variable therapeutic More than 30 various structures with variable therapeutic indication:indication:
sedatives (diazepam, alprazolam)sedatives (diazepam, alprazolam)hypnotics (nitrazepam, flunitrazepam), hypnotics (nitrazepam, flunitrazepam), antiepileptics (clonazepam)antiepileptics (clonazepam)
Shortly active – midazolam – introduction into anesthesia (halflife Shortly active – midazolam – introduction into anesthesia (halflife 1-4 h)1-4 h)
Long term active – diazepam – sedative (halflife 21-37 h)Long term active – diazepam – sedative (halflife 21-37 h)At overdose – accummulation in tissues, prolonged elimination At overdose – accummulation in tissues, prolonged elimination Extensive biotransformation – metabolites of phase I and IIExtensive biotransformation – metabolites of phase I and IIIdentification of toxic substance – important for differential Identification of toxic substance – important for differential
diagnosisdiagnosisPlasma level monitoring no correlation to effectPlasma level monitoring no correlation to effectAddictive substances at chronic use, development of toleranceAddictive substances at chronic use, development of toleranceLow mortality when related to barbituratesLow mortality when related to barbituratesAdditive sedation at combination with alcohol and sedative drugsAdditive sedation at combination with alcohol and sedative drugsComa state - Coma state - antidote flumazenil (ANEXAT)antidote flumazenil (ANEXAT), short halflife 40-60 , short halflife 40-60
minminGeneral danger at coma – vomit aspirationGeneral danger at coma – vomit aspiration
M. Balíková: Toxic compounds 27
AntidepressantsAntidepressantsTCA – tricyclic antidepressantsTCA – tricyclic antidepressants(amitriptyline, imipramine, trimipramine, clomipramine, dibenzepine…)Tetracyclic antidepressants Tetracyclic antidepressants – maprotiline, mianserineFrequent drugs at suicidal attemptsPacients with psychiatric treatment, endogenous depressions Lipophilic substances with protein bounds, large Vd At overdose – drug accumulation – prolonged effectNormetabolites more potent related to parent drug form
Therapeutic effect: CNS sedation, inhibition of neurotransmiters resorption Overdose:Overdose: cardiotoxicity, neurotoxicity
Symptoms of overdose:Cardivascular disturbances (hypotension)Coma, cramps, hyperthermiaRespiratory collaps, death
Therapy of overdoseSymptomatic proceduresHemoelimination, hemoperfusion
New types with lower toxicityNew types with lower toxicitySelective serotonin reuptake inhibitors fluoxetine, citalopram, sertraline, venlafaxine, paroxetine……….
M. Balíková: Toxic compounds 28
PhenothiazinesPhenothiazinesAntihistaminics – Antihistaminics – promethazine, dithiadeneNeuroleptics – Neuroleptics – chlorpromazine, levopromazine, chlorprothixene, thioridazine…………
Treatment of psychosesFrequent substances in overdose cases, suicidal attemptsLipophilic substances bounded to proteinsExtensive biotransformationAt overdose – accumulation in tissues, prolonged effect Antipsychotic effect, CNS sedation, affinity to neurotransmittersSymptoms of overdose:Delirium and comaTachycardia, bradycardia, arythmia, hypotoniaBreath center suppressionLife endargement: circulation and respiratory failureTherapy: symptomatic, sometimes physostigmine recommended
M. Balíková: Toxic compounds 29
MAO InhibitorsMAO InhibitorsMAO inhibitors – the first ones among antidepressivesStructurally hydrazines, hydrazides, amides, amines
MoclobemideMoclobemide (AURORIX)Extenzive oxidation, hydrolysisEffect mechanism:Interaction with catabolism of dopamine, noradrenaline, adrenaline, serotonine – with impact of neurotransmitters accumulation - serotonine syndromserotonine syndrom – endargement of hyperpyrexia and shockPotential interaction with other MAO inhibitors – amphetamines,TCASymptoms of overdose:similar to overdose by amphetamines, cocaine, caffeine ...
agitation, confusion, hallucination, convulsions, coma, cardiovascular disturbances – tachycardia, hypertension,
renal failure
Phentermin (ADIPEX)Treatment of obesiteMethamphetamine isomerAddictive potential
M. Balíková: Toxic compounds 30
Opiates and opioidesOpiates and opioidesOpiatesOpiates – alkaloides of natural origine and their structural synthetic analogs: morphine, codeine, dihydrocodeine, hydrocodone, oxycodone, pholcodine, ethylmorphine) – phenanthrene structure
OpioidesOpioides – – synthetic origine, another structure but similar effect, interaction with opioide CNS receptors: methadone, buprenorphine, tramadol, pethidine, fentanyl....NarcoticsNarcotics – in therapy part of analgetics, antitussives Abuse Abuse – illegal heroin – risk of fatal overdoseChronic abuse: somatic addiction, tolerance
Effects:Effects: Euphoria and sedation of CNS, miosis, suppressed intestine motility, constipation, respiration center suppression, coma, hypothermia, hypotonia, bradycardia, respiration and circulation collaps, deathSymptoms of fatal overdose: lung and brain edemaTherapyTherapy:Respiratory support, antidote naloxone, short halftime, repeated administration Naloxone – antagonist of opiate receptors – careful dosing – risk of abstinence syndrom
M. Balíková: Toxic compounds 31
Acetaminophen - ParacetamolAcetaminophen - ParacetamolPart of pharmaceutical products (COLDREX, KORYLAN, PANADOL…)Overdose– hepatotoxicityAssessment of hepatotoxic risk:
temporal profile of serum level after resorption (4 h after dose)
hepatoprotective antidotum – substance with SH groups(N-acetylcysteine)
M. Balíková: Toxic compounds 32
SalicylatesSalicylatesSalicineSalicine – – glycoside in willow-tree rind laic treatment of rheumatismAspirine, AcylpyrineAspirine, Acylpyrine – acetylsalicylic acidacetylsalicylic acidAntipyretics, analgetics, antiphlogistics, anticoagulantsMetabolism: hydrolysis, conjugation)Effect mechanism:Irreversibile inactivation of cyclooxygenase, local and systemic effectsToxic effects:Mucosal irritation, bleeding in GI, vomittingStimulation of respiratory center, disturbances in electrolytic and acidobasic balance, metabolic acidosis Rey syndrom in children with virosis: risk of encephalitis and hepatodamage, risk at susceptive asthmatics – abstinence from salicylates application
M. Balíková: Toxic compounds 33
TheophyllineTheophylline
Methylxantines: Methylxantines: Theophylline, caffeine – in coffee, teaTheobromine - cacao
Pharmaceutical products:Pharmaceutical products:Theophylline Theophylline (1,3-dimethylxanthine)(1,3-dimethylxanthine) – antiasthmaticum, bronchodilatator AminophyllineAminophylline – theophylline-ethylenediamineTheophylline- narrow terapeutic window
potential of overdoseSignificant plasma level monitoring (TDM)
Adverse effects, overdose, intoxication:CNS stimulationcardiovascular disturbances, arythmia (even fatal), convulsions, GI problems, vomiting , nausea
M. Balíková: Toxic compounds 34
CardiotonicsCardiotonicsGlycosides of digitalis Glycosides of digitalis DigoxineDigoxine (C (C4141HH6464OO1313), ), DigitoxineDigitoxine (C(C4141HH6464OO1414))
Cardiotonics – lipophilic substances, localized in myocardium, bonded to cardiac receptors, slow excretion. Digoxine excreted rather faster when related to digitoxine In cases of overdose – digoxine level in myocardium much higher than in plasma (100x). No correlation between effect to plasma levelTDM: control of therapeutic plasma level
Laboratory methods with respect to higher Mr (765, 781) – ICH, HPLC, not GCToxicita:Vomiting, nausea, confusion, visual disturbancesIon balance disturbance, hypokalemiaCardiac arythmia – life endargement, cardiac failureDigoxine fatal intoxication – death within 24 hoursDigitoxine fatal intoxication - dysrythmia prolonged to 5 days, prolonged toxic effects related to digoxine
M. Balíková: Toxic compounds 35
Pharmaceticals with cardiovascular effectsPharmaceticals with cardiovascular effectsDrugs affecting heart function directlyDrugs affecting heart function directly Heart glycosidesHeart glycosidesAntidysrythmics – Antidysrythmics – amiodarone, propafenol, verapamil, chinidine….amiodarone, propafenol, verapamil, chinidine….
Drugs affecting circulation systemDrugs affecting circulation systemAntihypertensivaAntihypertensivaCardioselective beta-blocking agents – Cardioselective beta-blocking agents – atenolol, metoprolol, labetalol, pindolol, sotalol, propafenone….atenolol, metoprolol, labetalol, pindolol, sotalol, propafenone….Diuretics – Diuretics – enhanced salts and water excretion– enhanced salts and water excretion– chlorothiazide, furosemide….chlorothiazide, furosemide….
Therapeutic indicationTherapeutic indication:: heart ischemia, arythmia,heart ischemia, arythmia, heart failure, cardiomyopatia,heart failure, cardiomyopatia, hypertensionhypertensionToxic effectsToxic effects:: dizziness, nausea, vasoconstriction, bradycardiadizziness, nausea, vasoconstriction, bradycardia bronchoconstriction, coronar spasms, hypotension, bronchoconstriction, coronar spasms, hypotension, cardiac and circulatory failure – life endargement, deathcardiac and circulatory failure – life endargement, death
M. Balíková: Toxic compounds 36
Abuse of addictive substancesAbuse of addictive substancesPharmaceuticals, illegal drugsPharmaceuticals, illegal drugs
CNS sedative substances, narcotics CNS sedative substances, narcotics opiates/opioids, benzodiazepinesopiates/opioids, benzodiazepines........
CNS stimulating substances:CNS stimulating substances:
amphetamines and derivatives, ephedrine, cocaine....amphetamines and derivatives, ephedrine, cocaine.... Substances affecting perception, psychedelics, hallucinogens:Substances affecting perception, psychedelics, hallucinogens:
PEA derivatives (MDMA, PMA, DOB, mescaline.....),PEA derivatives (MDMA, PMA, DOB, mescaline.....),tryptamine derivatives (harmine, dimethyltryptamine....) tryptamine derivatives (harmine, dimethyltryptamine....) ketamine, 9-THC, LSD, psilocybine, muscarine, atropine, ketamine, 9-THC, LSD, psilocybine, muscarine, atropine, scopolamine....... scopolamine.......
Tribe rituals - shaman leadership– application of natural Tribe rituals - shaman leadership– application of natural productsproducts
New trends – new synthetic drugs (NSD), dancing drugs New trends – new synthetic drugs (NSD), dancing drugs stimulating and psychedelic effects stimulating and psychedelic effects
PEA, tryptamine, piperazine structure analogues, PEA, tryptamine, piperazine structure analogues, synthetic cannabinoidssynthetic cannabinoids
NSD available via internet, frequent origine – Asia, ChinaNSD available via internet, frequent origine – Asia, China
Health risk of application of an illegal product – Health risk of application of an illegal product – no guarancy of its composition or content no guarancy of its composition or content
M. Balíková: Toxic compounds 37
Correlation of anamnesis and toxicology findingsCorrelation of anamnesis and toxicology findingsPacient Anamnestic
data Laboratory findings
M- 26 years
Deep coma, serious hypotensia, cardiac dysrythmia, anuria.
Assumpted: drug addict or epileptic
G: prothiaden (dothiepine) S: prothiaden 10590 ng/ml !!! S: northiaden 455 ng/ml (therapy 50- 150 ng/ml)
F- 20 years
Somnolent
Assumpted: Alcohol, I buprofen
B: ethanol 2,7 g/kg S: alprazolam 59 mg/ml (therapy 5- 50 ng/ml) G: ibuprofen+codeine+fluoxetine U: ibuprofen+metab.+ codeine+ fluoxetine+ salicylates+ caff eine
M- 21 years
Coma, convulsions U: methamphetamine+amphetamine+ephedrine+ bromazepam metabolites
F- 21 years
Coma, circulation failure, death - suicide Sectral 20 tbl.x 400mg = 8 g
G: acebutolol U: acebutolol + metabolites
M- 53 years
2 incidental gulps (cca 60 ml) of FRI DEX - 45 min before visiting a doctor and sampling for toxicology
S: EG 337 ng/ml U: EG 9640 ng/ml
G: gastric content; B: blood; S: serum; U: urine